Neural stem cell imaging program
Neural stem cells (NSCs) are defined by their ability to give rise to more stem cells by symmetric division (self-renewal) as well as to more mature progenitors of all neural lineages by asymmetric division (multipotentiality). Neural stem/progenitor cells capable of generating new neurons and glia, reside in specific areas of the adult mammalian central nervous system (CNS), including the ependymal region of the spinal cord and the subventricular zone (SVZ), hippocampus, and dentate gyrus of the brain. Both embryonic and adult NSCs have been shown to survive and spontaneously migrate to areas of lesion, most notably ischemic and neoplastic, differentiate in to different lineages and actively participate in repair, when transplanted in developing or adult brain in several mammalian species.
Despite the recent advances in therapeutic strategies, the prognosis for patients with brain tumors remains poor. Grafted NSCs can be used as cellular vehicles to deliver therapeutic proteins or genes via vectors for tumor treatment. We are using neural stem cells to populate primary tumors and their microsatelite deposits and also engineering NSCs (i) to secrete therapeutic protein, S-TRAIL (secreted Tumor necrosis factor receptor-apoptosis inducing ligand) to specifically induce apoptosis in tumor cells and (ii) regulatable anti-angiogenic proteins to inhibit tumor angiogenesis. However, one of the challenges in NSC transplantation is to determine the fate of cells after implantation and their migration to the diseased site.
We have explored the macroscopic migratory capabilities of NSCs towards experimental tumors following implantation into nude mice at distant sites in the brain. Using serial bioluminescence imaging, we have imaged the migration of NSCs towards lesions in the brain in real time (Shah and Tang et al., 2003; Kim et al., 2004). In a recent study we have shown that we can image both the migration of therapeutically engineered NSCs and the changes in glioma volumes in real time in live animals (Shah et al., 2005). The ability to image both the migration of NSCs and the changes in tumor volumes in vivo is critical in assessing the efficacy of gene delivery and in quantitating therapeutic effects. We are also developing viral vectors which express bioluminescent/fluorescent markers under neuronal cell type specific promoters to image differentiation of NSCs into terminal cell types in vivo.
Shah, K.*, Tang, Y*., Messerli, S.M., Breakefield, X.O. and Weissleder, R. In vivo tracking of neuronal progenitor cell migration in response to glioblastomas. Human Gene Therapy 2003, 14, 1247-1254 (*co- first authors)
Shah, K., Bureau, E., Kim, D. E., Yang, K, Tang, Y., Weissleder, R. and Breakefield X.O. Glioma therapy using a novel TRAIL secreting neural stem cells (NSCs) and in vivo tracking of NSC migration and tumor regression. Annals of Neurology 2005, 57, 34-41
Shah, K., Hsich, G. and Breakefield, X. O Neural stem cells and their role in neuro-oncology, Developmental Neuroscience, 2004, 26, 118-130
Kim, D., Schelingerhout, D., Ishi, K., Shah. K. and Weissleder, R. Imaging of stem cell recruitment to ischemic infarcts in a murine model. Stroke 2004, 35, 952-957